Modern techniques of pharmaceutical discovery often include assaying or screening immense test compound libraries to assess the effect of library members on specific target molecules or biological systems. Combinatorial chemistry and associated technologies for generating molecular diversity are significantly increasing the number of test compounds available for such screening. In addition, genomic research is elucidating vast numbers of new target molecules against which the efficacy of these test compounds may be screened. However, the search for lead compounds in the development of new pharmacological agents is frequently impeded by a lack of sufficient assay throughput. The sources of limited throughput include inadequate methods and devices for delivering sample materials, especially solution-phase samples, to assay detection devices, such as mass spectrometers for analysis. In particular, many preexisting sample delivery technologies lack sufficient automation to rapidly and reliably accommodate the enormous numbers of compounds in the libraries currently being produced.
Mass spectrometers are commonly used analytical instruments that provide qualitative and quantitative information about sample components. In addition to well established uses in analytical chemistry, mass spectrometry is commonly used as a tool in biology, e.g., for proteomics, nucleic acid sequencing and the like. In general, mass spectrometers are widely used to elucidate chemical structures of both inorganic and organic molecules, to determine molecular weights, and to ascertain isotopic ratios of atoms in samples. A mass spectrometric system typically includes a system inlet, an ion source, a mass analyzer, and a detector. The detector is generally operably connected to a signal processor and a computer. General sources of information about mass spectrometry include, e.g., Skoog, et al. Principles of Instrumental Analysis (5th Ed.) Hardcourt Brace & Company, Orlando (1998), Busch and Lehman, Guide to Mass Spectrometry, V C H Publishers, Inc. (1999), Watson, Introduction to Mass Spectrometry, 3rd, Lippincott-Raven Publishers (1997), Barker et al., Mass Spectrometry, 2nd, John Wiley & Sons, Inc. (1999), Stroobant, Mass Spectrometry: Principles and Applications, 2nd, John Wiley & Sons, Inc. (2001), Housby, Mass Spectrometry and Genomic Analysis, Kluwer Academic Publishers (2001), and Siuzdak, Mass Spectrometry for Biotechnology, Academic Press, Inc. (1996). Additional details relating to applications of mass spectrometry in combinatorial chemistry and pharmaceutical research are provided in, e.g., Kassel (2001) “Combinatorial chemistry and mass spectrometry in the 21st century drug discovery laboratory,” Chem. Rev. 101:255-267, Papac and Shahrokh (2001) “Mass spectrometry innovations in drug discovery and development,” Pharmaceut. Res. 18:131-145, Enjalbal et al. (2000) “Mass spectrometry in combinatorial chemistry,” Mass Spectrom. Rev. 19:139-161, Matsushita et al. (2000) “Identification of peptide superagonists using combinatorial chemistry and mass spectrometry,” Nihon Rinsho Meneki Gakkai Kaishi 23:571-576, Turteltaub and Vogel (2000) “Bioanalytical applications of accelerator mass spectrometry for pharmaceutical research,” Current Pharmaceutical Design 6:991-1007, Niessen (1999) “State-of-the-art in liquid chromatography-mass spectrometry,” J. Chromatogr. 856:179-197, Pramanik et al. (1999) “The role of mass spectrometry in the drug discovery process,” Curr. Opin. Drug. Disc. Develop. 2:401-417, Sussmuth and Jung (1999) “Impact of mass spectrometry on combinatorial chemistry,” Journal of Chromatography B 725:49-65, Swali et al. (1999) “Mass spectrometric analysis in combinatorial chemistry,” Curr. Opin. Chem. Biol. 3:337-341, and Unger (1999) “Using mass spectrometry to determine ADME properties in drug discovery,” Annu. Rep. Med. Chem. 34:307-316.
The formation of gaseous analyte ions for mass spectrometric analysis is generally accomplished using gas-phase or desorption ion sources. In particular, in a gas-phase ion source, a sample is first volatilized and then ionized. In contrast, solid- or liquid-phase samples, which often include nonvolatile or thermally unstable compounds, are directly converted into gaseous ions in desorption ion sources. One widely used desorption technique, especially for analyzing biopolymers or other species in excess of 100,000 daltons (Da), is electrospray ionization. Electrospray ionization, which can occur at atmospheric pressures and temperatures, is generated when a sufficient electrical potential difference is applied between a conductive or partly conductive fluid exiting, e.g., a capillary opening and an electrode so as to produce a concentration of electric field lines emerging from the capillary opening. When a positive voltage is applied to the capillary opening relative to, e.g., an extracting electrode at an ion-sampling orifice of a mass spectrometer, the electric field causes positively-charged ions in the fluidic sample to migrate to the surface of the fluid at the capillary opening. Negatively-charged ions will migrate to the fluid surface at the capillary opening, when a negative voltage is applied to the capillary opening relative to the extracting electrode. When the repulsive force of the ions at the fluid surface exceeds the surface tension of the fluid sample, a volume of the fluid forms a Taylor cone that extends from the capillary tip and charged droplets are drawn toward the extracting electrode. The resulting charged spray of fine droplets undergoes solvent evaporation and attachment of charge to analyte molecules in the droplets. As the charged droplets decrease in size due to the evaporation of solvent, their charge density increases such that ions are desorbed into the gaseous-phase. Significantly, the electrospray process typically produces only limited fragmentation of, e.g., large and thermally fragile biopolymers such that resultant mass spectra are greatly simplified relative to those generated using harder ion sources and often include only molecular ions or protonated molecular ions. Furthermore, electrospray ion sources are typically readily adapted to direct sample introduction into inlet systems following various upstream processing steps, including chromatographic (e.g., HPLC, etc.) and electrophoretic (e.g., capillary electrophoresis, etc.) separations. Additional information relating to electrospray ionization is described in, e.g., Cole (Ed.), Electrospray Ionization Mass Spectrometry: Fundamentals, Instrumentation and Applications, John Wiley & Sons, Inc. (1997) and Snyder (Ed.), Biochemical and Biotechnological Applications of Electrospray Ionization Mass Spectrometry, American Chemical Society (1995).
Preexisting apparatus and techniques generally lack sufficient automation and throughput to efficiently deliver significant numbers of fluidic samples, such as those produced by combinatorial synthesis, to detection devices for analysis or to other sample destinations. As a consequence, improved devices, systems, and methods of such fluid delivery would be desirable. More specifically, improved apparatus and methods for electrospraying fluidic samples for mass spectrometric or other gas-phase analyses would be particularly desirable. The present invention is directed to these and other features by providing automated, high-throughput microfluidic sample delivery devices or systems and to methods of using the same. These and many other attributes will be apparent upon complete review of the following disclosure.